Antilipemic Agents
The present invention relates to an antilipemic agent containing a lignan
analog and an HMG-CoA reductase inhibitor. Background Art Methyl
1-(3,4-dimethoxyphenyl)-3-(ethylvaleryl)-4-hydroxy-6,7,8-
trimethoxy-2-naphthoate (hereinafter referred to as compound A) is a lignan
analog possessing an antilipemic activity based on the inhibition of the
re-absorption of bile acid in the small intestine (JP Patent publication (Kokai)
93/310634, corresponding USP 5,420,333, "Asunoshinyaku" 2000 year (Technomics),
Life Sci. 1997, 60: PL365, J. Pharmacol. Exp. Ther. 1998, 284: 43, Arterioscler.
Thromb. Vasc. Biol. 1998, 18: 1304). A glucuronic acid conjugate thereof (e.g.,
[1-0-{4-(3,4-dimethoxyphenyl)-2-(3-ethylpentanoyl)-5,6,7-tri
methoxy-3-(methoxycarbo nylnaphthalene-1-yl}- beta -D-glucopyranoside] uronic
acid) is also known as possessing the antilipemic activity (JP Patent
publication (Kokai) 97/241206).
In contrast, 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase
inhibitor inhibits specifically HMG-CoA reductase, a rate-limiting enzyme in the
cholesterol biosynthesis, so as to suppress the synthesis of cholesterol, thus
being effective for the treatment of hypercholesterolemia, hyperlipoproteinemia,
atherosclerosis and the like (Am. J. Med. 1998, 104(2A): 19S).
WO 98/40375 refers to an antilipemic agent containing a bile acid
re-absorption inhibitor such as benzothiazepines and an HMG-CoA reductase
inhibitor, without disclosing any concrete data of the antilipemic activity as
expected upon the combination use of the both inhibitors.
Further, Arterioscler Thromb Vasc Biol. 1998; 18: 1304-1311 (Inhibition of
Ileal Na+ / Bile Acid Cotransporter by S-8921 Reduces Serum Cholesterol and
Prevents Atherosclerosis in Rabbits) reports that oral administration of
compound A to rabbits increased the HMG-CoA reductase activity in the liver,
without mentioning any concrete data of a therapeutic effect upon the
combination use of an HMG-CoA reductase inhibitor.
Accordingly, it has been desired to develop a more effective method for the
prevention or treatment of hyperlipemia using compound A or the like, as well as
a pharmaceutical composition therefor. Disclosure of Invention
The present inventors have found that use of a HMG-CoA reductase inhibitor in
combination with the above described compound A or a glucuronic acid conjugate
thereof can lower the cholesterol concentration in blood more significantly than
single use of the HMG-CoA reductase inhibitor, whereby to accomplish the present
invention shown below. (1) An antilipemic agent, which contains methyl
1-(3,4'dimethoxyphenyl)-3'(3-ethylvaleryl)-4-hydroxy-6,7,8-t
rimethoxy-2-naphthoate, a glucuronic acid conjugate thereof, their salt, or a
solvate thereof and an HMG-CoA reductase inhibitor.
(2) The antilipemic agent according to above (1), wherein the HMG-CoA
reductase inhibitor is mevastatin, pravastatin, BMY-22089, colestrone,
lovastatin, crilvastatin, dalvastatin, SC-45355, simvastatin, acitemate,
BMS-180431, SQ-33600, CP-83101, BB-476, BMY-21950, L-669262, fluvastatin,
itavastatin, glenvastatin, S-2468, cerivastatin, DMP-565, atorvastatin,
bervastatin, rosuvastatin, carvastatin, U-20685, HBS-107, BAY-x-2678 or
BAY-10-2987. (3) The antilipemic agent according to above (1), wherein the
HMG-CoA reductase inhibitor is pravastatin. (4) An agent for enhancing the
antilipemic effect of an HMG-CoA reductase inhibitor, which contains methyl
1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-t
rimethoxy-2-naphthoate, a glucuronic acid conjugate thereof, their salt or a
solvate thereof.
(5) Use of methyl
1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-t
rimethoxy-2-naphthoate, a glucuronic acid conjugates thereof, their salt or a
solvate thereof for enhancing the antilipemic effect of an HMG-CoA reductase
inhibitor. (6) A preventive or therapeutic method for hyperlipemic disease,
which comprises administrating methyl
1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-t
rimethoxy-2-naphthoate, a glucuronic acid conjugates thereof, their salt or a
solvate thereof in combination with an HMG-CoA reductase inhibitor. Brief
Description of Drawings
This graph shows a hypocholesterolemic effect in WHHL rabbits. The horizontal
axis represents time (week) after the start of administration of a medicine and
the vertical axis represents a change of the cholesterol level in the
medicine-administered group compared with that of the control group. Best Mode
for Carrying Out the Invention
A glucuronic acid conjugate of compound A (methyl
1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-t
rimethoxy-2-naphthoate) means preferably
[1-0-{4-(3,4-dimethoxyphenyl)-2-(3-ethylpentanoyl)-5,6,7-tri
methoxy-3-(methoxycarbo nyl) naphthalene-1-yl}- beta -D-glucopyranoside] uronic
acid.
A salt of compound A or glucuronic acid conjugate thereof means preferably a
pharmaceutically acceptable salt. Examples thereof include alkaline metal salts
(e.g., Na, K), alkaline earth metal salts (e.g., Ca, Mg), amine salts (e.g.,
n-butylamine, sec-butylamine, i-propylamine, triethylamine, phenylamine,
diphenylamine, N-phenyl-N-methylamine, pyridine, piperidine, morpholine,
N-methylpiperidine, N-methyl morpholine). Examples of solvent of a solvate
include alcohol and water.
In the present description, compound A, a glucuronic acid conjugate and a
solvate thereof may be hereinafter collectively referred to as "lignan analog" .
Examples of HMG-CoA reductase inhibitor include those described in WO
98/40375, "Asunoshinyaku" (Technomics) and the like, and preferred are
mevastatin, pravastatin, BMY-22089
(trans-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5- yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one),
colestrone, lovastatin, crilvastatin, dalvastatin, SC-45355, simvastatin,
acitemate, BMS-180431
(trans-6(S)-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol
-5-yl)-1,3-butadienyl]tetrahydro-4-hyd roxy-2H-pyran-2-one), SQ-33600
((S)-4-[[[1-(4-fluorophenyl)-3-(1- methylethyl)-1H-indol-2-yl]ethynyl]hydroxyphosphinyl]-3-hydr
oxybutanoic acid, disodium salt), CP-83101 (methyl
(3R,5S)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoate), BB-476, BMY-21950
(sodium (+/-)-erythro-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-met
hyl-1H-tetrazol-5-yl)-6,8-nonadienoate), L-669262 (1,2,6,7,8,
8a-hexahydro-3,7-dimethyl-6-oxo-8-[2-(tetrahydro-4-hydrox y-6-oxo-2H-pyra
n-2-yl)ethyl]-1-naphthalenyl[1S-[1 alpha ,7 beta ,8 beta (2S*,4S*),8a beta
]]-2,2-dimethyl-butanoic acid), fluvastatin, itavastatin, glenvastatin, S-2468,
cerivastatin, DMP-565, atorvastatin, bervastatin, rosuvastatin (ZD-4522),
carvastatin, U-20685 (17-hydroxyimino-1,3,5(10)-estratriene-3-ol), HBS-107,
BAY-x-2678 or BAY-10-2987.
Preferred are pravastatin, lovastatin, simvastatin, fluvastatin, itavastatin,
cerivastatin, atorvastatin, rosuvastatin (ZD-4522), HBS-107, BAY-x-2678,
BAY-10-2987 and the like, more preferred are statin-type compounds having, as a
side chain, 3,5-dihydroxycarboxylic acid or the lactone form, such as
pravastatin, lovastatin, simvastatin, fluvastatin, itavastatin, cerivastatin,
atorvastatin, rosuvastatin, esp. pravastatin and rosuvastatin.
The antilipemic agent of the present invention containing the above-described
lignan analog and HMG-CoA reductase inhibitor may be in any formulation
including e.g., granules, complex granules, powders, tablets, capsules, complex
capsules. These formulations may contain an appropriate amount of well known
medicinal additives such as binders, excipients, disintegrators, and
dispersants.
Examples of the amount ratio of the above lignan analog and HMG-CoA reductase
inhibitor includes, but not limited thereto: preferably compound A : HMG-CoA
reductase inhibitor = 1:500 to 500:1, more preferably 1:50 to 50:1, and most
preferably 1:10 to 10:1, by mol.
The above antilipemic agent can be preferably administrated orally. The daily
dose for an adult is the lignan analog about 0.01 to 50 mg/kg, preferably about
0.1 to 30 mg/kg and HMG-CoA reductase inhibitor about 0.001 to 30 mg/kg,
preferably about 0.01 to 10 mg/kg.
The combination use of the above lignan analog and HMG-CoA reductase
inhibitor can bring more potent antilipemic effects than each single use. Thus,
the composition of the present invention containing both is useful as a
preventive or therapeutic agent for hyperlipemic disease.
The method for the above combination use may be, but not limited thereto, a
simultaneous administration or time-lapse administration. The administered
composition(s) may be single unit formulation or separated-type formulations.
Their dose ratio is in accordance with the above mentioned one.
Further, the present invention provides an agent for enhancing the
antilipemic effect of an HMG-CoA reductase inhibitor, which contains the above
mentioned lignan analog, as well as use of the lignan analog for enhancing the
antilipemic effect of an HMG-CoA reductase inhibitor. The dose ratio of the
lignan analog per the HMG-CoA reductase inhibitor and each dose may be in
accordance with the above mentioned one. Examples of the enhancing agent include
a formulation enhancing the inhibitory activity itself of an HMG-CoA reductase
inhibitor, as well as a formulation which can, even when possessing little or no
such a direct enhancing effect to an HMG-CoA reductase inhibitory activity,
consequently enhance the antilipemic effect of the co-used HMG.CoA reductase
inhibitor.
Examples of the present invention are shown below. Formulation Example 1
Compound A (methyl1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-
6,7,8-trimethoxy-2- naphthoate) and pravastatin are mixed and granulated
together with mannitol, carmellose calcium, and hydroxypropyl cellulose each in
a proper amount, to prepare granules. Formulation Example 2
A glucuronic acid conjugate of compound A and lovastatin are mixed and
granulated together with mannitol, carmellose calcium and hydroxypropyl
cellulose each in a proper amount, to prepare granules. Formulation Example 3
A mixture of the granule of Formulation Example 1 or 2 and stearic acid is
capsulated into a hard capsule to prepare capsules. Formulation Example 4
Compound A is mixed and granulated together with mannitol, carmellose calcium
and hydroxypropyl cellulose each in a proper amount to prepare an agent for
enhancing the effect of rosuvastatin. Test Example 1
WHHL rabbits, 24-weeks old were divided into the following groups. 1)
non-treated control group (n=7; 3 males and 4 females) 2) group administered
with Compound A 10 mg/kg/day (n=6; 2 males and 4 females) 3) group administered
with pravastatin 3 mg/kg/day (n=6; 2 males and 4 females) 4) group
co-administered with Compound A and pravastatin (n=7; 3 males and 4 females)
The test was conducted over 8 weeks including 6 weeks of administration and
next 2 weeks of drug withdrawal, by collecting blood at intervals to measure the
concentration of serum cholesterol. Any drug was administered as a mixture with
food.
The results are shown in Fig. 1, wherein each line shown of &cir& , DELTA ,
&squ& and &cirf& corresponds to the above groups 1) to 4), respectively.
The co-administration of compound A with pravastatin more significantly
lowered the cholesterol level than single use of pravastatin. In particularly,
at 4 weeks after the start of co-administration, the cholesterol lowering was 3
times as strong compared with that by the single use of pravastatin. Test
example 2
Each formulation of Formulation Examples 1 to 3 is administered to rabbits
according to Test Example 1, to confirm the cholesterol-lowering effect.
Industrial Applicability
The combination use of an HMG-CoA reductase inhibitor and a lignan analog of
the present invention is effective for the prevention or treatment of
hyperlipemic disease.
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